The Combination of Pulsatile and Switch-Like Behaviors of p53 in Response to DNA Damage

Abstract

Upon DNA damage, p53 is stabilized and activated to induce diverse cellular outcomes including cell cycle arrest and apoptosis. The p53 dynamics can exhibit distinct modes, depending on cell and stress types. In an analog mode, high (low) levels of p53 lead to cell death (survival) in response to lethal (sublethal) DNA damage. By contrast, p53 levels exhibit a series of discrete pulses in a digital mode, wherein it is the number of p53 pulses that determines the cell fate [1]. Here, we explore whether both the modes of p53 are exploited in one cellular response. We propose a modular model for the cell fate decision between survival and death, which is governed by the p53 network. At low damage levels, p53 levels exhibit few pulses, and the cell returns to normal proliferation after DNA damage is fixed. For irreparable damage, the amount of p53 first displays four pulses and then switches to high levels, and the cell undergoes apoptosis. The negative feedback loop between p53 and Mdm2 and that between ATM and p53 via Wip1 are responsible for p53 oscillations, whereas the switching behavior occurs when the positive feedback loop between p53 and PTEN predominates over the negative feedback loops. Such a combination of pulsatile and switch-like behaviors of p53 may represent a flexible and reliable control mode, avoiding unnecessary cell death or promoting execution of apoptosis. This work also underscores that both the nature and strength of feedback loops determine p53 dynamics.[1] X.-P. Zhang, F. Liu, Z. Cheng, and W. Wang (2009) Cell fate decision mediated by p53 pulses. Proc. Natl. Acad. Sci. USA. 106, 12245-12250.